NO883381L - PROCEDURE FOR THE PREPARATION OF N - (((4-HYDROSY-PYRROLIDIN-2-ON-1-YL) -ACETYL) -GYLCINAMIDE. - Google Patents
PROCEDURE FOR THE PREPARATION OF N - (((4-HYDROSY-PYRROLIDIN-2-ON-1-YL) -ACETYL) -GYLCINAMIDE.Info
- Publication number
- NO883381L NO883381L NO88883381A NO883381A NO883381L NO 883381 L NO883381 L NO 883381L NO 88883381 A NO88883381 A NO 88883381A NO 883381 A NO883381 A NO 883381A NO 883381 L NO883381 L NO 883381L
- Authority
- NO
- Norway
- Prior art keywords
- acetyl
- alkyl ester
- glycine
- pyrrolin
- temperatures
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 13
- -1 4-hydroxy-pyrrolidin-2-on-1-yl Chemical group 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 239000004471 Glycine Substances 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 9
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- 125000005907 alkyl ester group Chemical group 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 150000004678 hydrides Chemical class 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000013067 intermediate product Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- CVIXOOVAHSWDMO-UHFFFAOYSA-N 2-amino-N-[2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetyl]acetamide Chemical compound OC1CC(N(C1)CC(=O)NC(CN)=O)=O CVIXOOVAHSWDMO-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- JNYMRXDQVPIONI-HWKANZROSA-N methyl (e)-4-chloro-3-methoxybut-2-enoate Chemical compound COC(=O)\C=C(/CCl)OC JNYMRXDQVPIONI-HWKANZROSA-N 0.000 description 2
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BMOXYLBGPIDAAN-UHFFFAOYSA-N 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid Chemical compound OC1CN(CC(O)=O)C(=O)C1 BMOXYLBGPIDAAN-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229960001227 oxiracetam Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Abstract
Hytt 4-hydrokay-2-pyrrolidinonderivat oa*t fremgangsmåt* for frettstilling av detta.Cabin 4-hydrokay-2-pyrrolidinone derivative oa * t method * for removing it.
Description
Oppfinnelsen angår en ny fremgangsmåte for fremstilling av N-[(4-hydroksy-pyrrolidin-2-on-l-yl)-acetyl]-glycinamid, en analog til cerebral-virksomt oksiracetam (4-hydroksy-pyrrolidin-2-on-l-yl-acetamid), sistnevnte kjent fra Pifferi et al, Il Farmaco, Ed.Sc. 1977, 32, 602. The invention relates to a new process for the production of N-[(4-hydroxy-pyrrolidin-2-on-l-yl)-acetyl]-glycinamide, an analogue of cerebrally active oxiracetam (4-hydroxy-pyrrolidin-2-on- 1-yl-acetamide), the latter known from Pifferi et al, Il Farmaco, Ed.Sc. 1977, 32, 602.
Fra europeisk patent A 0 2 07 681 er det kjent to fremgangsmåter for fremstilling av N-[(4-hydroksypyrrolidin-2-on-l-yl)-acetyl]-glycinamid. Ifølge den første fremgangsmåte sykliseres en 2-metylpropyl-3-karbamoylmetyl-beta-hydroksy-2-(1-metyletyl)-4-okso-l-imidazolidinbutansyreester i nærvær av vann intramole-kylært til sluttproduktet. From European patent A 0 2 07 681 two methods are known for the production of N-[(4-hydroxypyrrolidin-2-on-1-yl)-acetyl]-glycinamide. According to the first method, a 2-methylpropyl-3-carbamoylmethyl-beta-hydroxy-2-(1-methylethyl)-4-oxo-1-imidazolidinebutanoic acid ester is cyclized in the presence of water intramolecularly to the final product.
Ifølge den annen fremgangsmåte omsettes dessuten 4-hydroksy-2-okso-l-pyrrolidineddiksyre med glycinamid. According to the second method, 4-hydroxy-2-oxo-1-pyrrolidineacetic acid is also reacted with glycinamide.
Begge fremgangsmåter utmerker seg på ufordelaktig måte ved meget omstendelige fremgangsmåteformer, som ikke er tenkelig i stor teknisk målestokk. Both methods are disadvantageously distinguished by very cumbersome method forms, which are not conceivable on a large technical scale.
Det var derfor en oppgave å finne en ny enkel fremgangsmåte som kunne anvendes i stor teknisk målestokk, og som ikke har de nevnte ulemper. It was therefore a task to find a new simple method that could be used on a large technical scale, and which does not have the aforementioned disadvantages.
Oppgaven kunne løses med en fremgangsmåte omfattende føl-gende trinn: a) omsetting av en (4-halogen-3-alkoksy-but-2E-ensyrealkyl-ester) med en glycinglycinalkylester til en N-[(4-alkoksy-3- pyrrolin-2-on-l-yl)acetyl]-glycinalkylester, b) videre omsetting med benzylalkohol i nærvær av en syre, midlertidig til N-[(4-benzyloksy-3-pyrrolin-2-on-l-yl)-acetyl]-glycinalkylester, c) amidering med ammoniakk til N-[(4-benzyloksy-3-pyrrolin-2-on-l-yl)-acetyl]-glycinamid, d) avspalting av den beskyttende benzylgruppe ved hydrogenolyse i nærvær av en palladiumkatalysator med hydrogen, The task could be solved with a method comprising the following steps: a) conversion of a (4-halo-3- alkoxy-but-2E-enoic acid alkyl ester) with a glycine glycine alkyl ester to a N-[(4-alkoxy-3-pyrroline -2-on-l-yl)acetyl]-glycine alkyl ester, b) further reaction with benzyl alcohol in the presence of an acid, temporarily to N-[(4-benzyloxy-3-pyrrolin-2-on-l-yl)-acetyl ]-glycine alkyl ester, c) amidation with ammonia to N-[(4-benzyloxy-3-pyrrolin-2-on-1-yl)-acetyl]-glycinamide, d) removal of the protective benzyl group by hydrogenolysis in the presence of a palladium catalyst with hydrogen,
og til sluttand finally
e) reduksjon med et komplekst hydrid.e) reduction with a complex hydride.
Trinn a)Step a)
4- Halogen-3-alkoksy-but-2E-ensyrealkylesteren som anvendes som utgangsprodukt, kan hensiktsmessig fremstilles ifølge europeisk patent A 0 216 324 på enkel måte. The 4-halo-3-alkoxy-but-2E-enoic acid alkyl ester which is used as starting product can conveniently be prepared according to European patent A 0 216 324 in a simple way.
Med fordel anvendes 4-klor-3-(C-l-C2 ) -alkoksy-but-2E-ensyre-( C^ C^)-alkylesteren som utgangsprodukt, men 4-klor-3-metoksy-but-2E-ensyremetylesteren er spesielt foretrukket. The 4-chloro-3-(C-1-C2 )-Alkoxy-but-2E-enoic acid-(C1-C2)-alkyl ester is advantageously used as starting product, but the 4-chloro-3-methoxy-but-2E-enoic acid methyl ester is particularly preferred.
Som glycinglycinalkylester anvendes fortrinnsvis en (C^-C4)-laverealkylester, idet etylesteren, vanligvis i form av hydrokloridet, er spesielt foretrukket. A (C 1 -C 4 )-lower alkyl ester is preferably used as the glycine glycine alkyl ester, the ethyl ester, usually in the form of the hydrochloride, being particularly preferred.
Omsetningen skjer hensiktsmessig i nærvær av et tertiært amin, fortrinnsvis et trialkylamin, såsom trietylamin, ved temperaturer på mellom 50 og 80°C, fortrinnsvis ved 80°C. Det er likeledes fordelaktig å arbeide i cyaniderte hydrokarboner, fortrinnsvis i acetonitril, som løsningsmiddel. N-[(4-Alkoksy-3-pyrrolin-2-on-l-yl)-acetyl]-glycinalkylesteren som fremkommer etter en reaksjonstid på 4-8 timer, kan isoleres ifølge vanlig laboratoriepraksis fra reaksjonsblandingen og eventuelt renses. The reaction conveniently takes place in the presence of a tertiary amine, preferably a trialkylamine, such as triethylamine, at temperatures of between 50 and 80°C, preferably at 80°C. It is likewise advantageous to work in cyanidated hydrocarbons, preferably in acetonitrile, as solvent. The N-[(4-Alkoxy-3-pyrrolin-2-on-1-yl)-acetyl]-glycine alkyl ester which appears after a reaction time of 4-8 hours can be isolated according to normal laboratory practice from the reaction mixture and optionally purified.
Trinn b og cSteps b and c
Trinn b og c utføres hensiktsmessig uten isolering av mellomproduktet fra trinn b i ett trinn. Selvfølgelig kan imid-lertid også isolasjon av mellomproduktet ifølge b) utføres trinnvis. Steps b and c are conveniently carried out without isolating the intermediate from step b in one step. Of course, however, isolation of the intermediate product according to b) can also be carried out in stages.
Benzylalkoholen tilsettes fortrinnsvis i et overskudd på 3-10 mol pr. mol til utgangsproduktet fra trinn a). Dessuten fungerer benzylalkoholen samtidig som løsningsmiddel for trinn The benzyl alcohol is preferably added in an excess of 3-10 mol per mol to the starting product from step a). In addition, the benzyl alcohol also acts as a solvent for steps
b) . b).
Som syre tilsettes i katalytiske mengder hensiktsmessig 5-20 mol% av en sulfonsyre, såsom for eksempel metansulfonsyre eller p-toluensulfonsyre. As acid, 5-20 mol% of a sulphonic acid, such as for example methanesulphonic acid or p-toluenesulphonic acid, is added in catalytic amounts.
Omsetningstemperaturen for innføring av de beskyttende benzylgrupper ligger hensiktsmessig på 80-120°C, fortrinnsvis 90-100°C. The reaction temperature for introducing the protective benzyl groups is suitably 80-120°C, preferably 90-100°C.
Reaksjonen utføres fortrinnsvis ved et lett undertrykk på 5-100 mbar. Herved er man sikker på at de avspaltede alkoholer med lavt kokepunkt ved denne omsetning fjernes fra likevekts-blandingen. The reaction is preferably carried out at a slight negative pressure of 5-100 mbar. This ensures that the separated alcohols with a low boiling point are removed from the equilibrium mixture during this reaction.
Etter en reaksjonstid på ca. 4 timer kan den intermediært foreliggende benzyloksypyrrolinester amideres direkte, uten isolering. Reaksjonsoppløsningen blir samtidig hensiktsmessig, eventuelt etter ytterligere fortynning, fortrinnsvis med en alkohol såsom f.eks. metanol, mettet med ammoniakk. After a reaction time of approx. 4 hours, the intermediately present benzyloxypyrroline ester can be amidated directly, without isolation. The reaction solution becomes appropriate at the same time, possibly after further dilution, preferably with an alcohol such as e.g. methanol, saturated with ammonia.
Ved temperaturer på 20-80°C kan reaksjonen betraktes som ferdig etter ca. 8-12 timer. At temperatures of 20-80°C, the reaction can be considered complete after approx. 8-12 hours.
Etter vanlig laboratoriemessig opparbeidelse og eventuelt etter ytterligere rensning kan N-[(4-benzyloksy-3-pyrrolin-2-on-l-yl)-acetyl]-glycinamidet oppnås. After usual laboratory work-up and possibly after further purification, the N-[(4-benzyloxy-3-pyrrolin-2-on-1-yl)-acetyl]-glycinamide can be obtained.
Trinn d og eSteps d and e
Trinn d og e utføres hensiktsmessig i ett trinn, uten at man isoleres mellomproduktet fra trinn d). Avspaltingen av de beskyttende benzylgrupper skjer i nærvær av en palladiumkatalysator i mengder på 5-20 vekt%, basert på anvendt utgangsprodukt, tilveiebrakt på en vanlig bærer, fortrinnsvis på kull med hydrogen. Steps d and e are suitably carried out in one step, without isolating the intermediate product from step d). The removal of the protective benzyl groups takes place in the presence of a palladium catalyst in amounts of 5-20% by weight, based on the starting product used, provided on a common support, preferably on carbon with hydrogen.
Man arbeider hensiktsmessig ved temperaturer på 0-30°C og trykk på 1-10 bar. One works appropriately at temperatures of 0-30°C and pressure of 1-10 bar.
Det er fordelaktig å arbeide i et aprotisk løsningsmiddel med høyere dielektrisitetskonstanter, såsom dimetylacetamid eller dimetylformamid. It is advantageous to work in an aprotic solvent with higher dielectric constants, such as dimethylacetamide or dimethylformamide.
Etter 1-5 timer kan hydrogenolysen betraktes som ferdig. After 1-5 hours, the hydrogenolysis can be considered complete.
Mellomproduktet N-[(2,4-diokso-pyrrolidin-l-yl)-acetyl]-glycinamid isoleres ikke; hensiktsmessig reduseres det umiddel-bart videre med et komplekst hydrid til sluttproduktet. Som komplekse hydrider anvendes hensiktsmessig alkaliborhydridene, fortrinnsvis natriumborhydridet. The intermediate N-[(2,4-dioxo-pyrrolidin-1-yl)-acetyl]-glycinamide is not isolated; expediently, it is immediately further reduced with a complex hydride to the final product. The alkali borohydrides, preferably sodium borohydride, are suitably used as complex hydrides.
Omsetningstemperaturen velges hensiktsmessig mellom 0 og 30°C. The reaction temperature is suitably chosen between 0 and 30°C.
Fra reaksjonsblandingen kan man etter vanlig opparbeidelse få sluttproduktet N-[(4-hydroksy-pyrrolidin-2-on-l-yl)-acetyl]-glycinamid, eventuelt etter rensning, som hvitt krystallinsk produkt. From the reaction mixture, the end product N-[(4-hydroxy-pyrrolidin-2-on-l-yl)-acetyl]-glycinamide can be obtained after normal work-up, possibly after purification, as a white crystalline product.
EksempelExample
a) Fremstilling av N- f f4- metoksy- 3- pvrrolin- 2- on- l- yl)-acetyl"[ - glycinetylester a) Preparation of N-ff4-methoxy-3-pyrrolin-2-on-l-yl)-acetyl"[- glycine ethyl ester
25,6 g (0,13mol) glycinglycinetylester-hydroklorid ble suspendert i 60 ml acetonitril. Til dette ble det under til-bakeløp tilsatt 13,2 g (0,13 mol) trietylamin. Deretter ble det etter hverandre i løpet av 4 timer dryppet til 17,2 g (0,1 mol) 4-klor-3-metoksy-but-2E-ensyremetylester og 10,2 g (0,1 mol) trietylamin i flere porsjoner. 25.6 g (0.13 mol) of glycine glycine ethyl ester hydrochloride was suspended in 60 ml of acetonitrile. To this, 13.2 g (0.13 mol) of triethylamine were added under reflux. Then, over the course of 4 hours, 17.2 g (0.1 mol) of 4-chloro-3-methoxy-but-2E-enoic acid methyl ester and 10.2 g (0.1 mol) of triethylamine were added dropwise in several portions .
Løsningsmidlet ble avdestillert på rotasjonsfordamper og man fikk 150 ml vann som rest. Den vandige oppløsning ble ekstrahert 4 ganger med 50 ml metylenklorid hver gang. The solvent was distilled off on a rotary evaporator and 150 ml of water was obtained as a residue. The aqueous solution was extracted 4 times with 50 ml of methylene chloride each time.
Metylenklorid-fasen ble fraskilt, tørket over natriumsul-fat og inndampet. The methylene chloride phase was separated, dried over sodium sulfate and evaporated.
Man fikk 21,9 g råprodukt.21.9 g of crude product was obtained.
En prøve som ble omkrystallisert fra toluen, hadde et smeltepunkt på 87,5-88,5°C. A sample recrystallized from toluene had a melting point of 87.5-88.5°C.
b) c) Fremstillin<g>av N-(" ( 4- benzyloksy- 3- pyrrolin- 2- on- l- yl) - acetyl]- glycinamid b) c) Preparation<g>of N-(((4-benzyloxy-3-pyrrolin-2-on-1-yl)-acetyl]- glycinamide
4,7 g (18,4 mmol) N-[(4-metoksy-3-pyrrolin-2-on-l-yl)-acetyl]-glycinetylester ble oppløst i 10,8 g (100 mmol) benzylalkohol og tilsatt 0,1 g (1 mmol) metansulfonsyre. Denne reak-sjonsblanding ble omrørt i 4 timer ved 100°C og ved 20 mbar. Deretter tilsatte man 2 0 ml metanol og mettet reaksjonsoppløs-ningen med gassformig ammoniakk. Det ble omrørt ved 60°C over natten, og deretter ble metanol og benzylalkohol avdestillert i vakuum. Residuet ble omkrystallisert fra metanol. 4.7 g (18.4 mmol) of N-[(4-methoxy-3-pyrrolin-2-on-1-yl)-acetyl]-glycine ethyl ester was dissolved in 10.8 g (100 mmol) of benzyl alcohol and added 0 .1 g (1 mmol) methanesulfonic acid. This reaction mixture was stirred for 4 hours at 100°C and at 20 mbar. 20 ml of methanol were then added and the reaction solution was saturated with gaseous ammonia. It was stirred at 60°C overnight, and then methanol and benzyl alcohol were distilled off in vacuo. The residue was recrystallized from methanol.
Man fikk 4,5 g N-[(4-benzyloksy-3-pyrrolin-2-on-l-yl)-ace-tyl] -glycinamid. Smp. 169-170°C. 4.5 g of N-[(4-benzyloxy-3-pyrrolin-2-on-1-yl)-acetyl]-glycinamide were obtained. Temp. 169-170°C.
<C>15<H>17N3°4(303,32) beregnet C 59,4 H 5,6 N 13,9 <C>15<H>17N3°4(303.32) calculated C 59.4 H 5.6 N 13.9
funnet C 59,0 H5,7 N 14,0found C 59.0 H5.7 N 14.0
d)e) Fremstilling av N- r( 4- hvdroksv- pyrrolidin- 2- on- l- yl)-acetyl]- glycinamid d)e) Preparation of N-r(4-hydroxy-pyrrolidin-2-on-1-yl)-acetyl]- glycinamide
4,0 g (13,2 mmol) N[(4-benzyloksy-3-pyrrolin-2-on-l-yl)-acetyl]-glycinamid ble oppløst i 50 ml dimetylacetamid og tilsatt 0,4 g palladium på kull 5%. 4.0 g (13.2 mmol) of N[(4-benzyloxy-3-pyrrolin-2-on-l-yl)-acetyl]-glycinamide was dissolved in 50 ml of dimethylacetamide and 0.4 g of palladium was added on charcoal 5 %.
Denne blanding ble hydrogenolysert i 4 timer ved 4 bar ogThis mixture was hydrogenolyzed for 4 hours at 4 bar and
i romtemperatur med hydrogen. Deretter ble katalysatoren fraskilt ved hjelp av filter med sug og reaksjonsoppløsningen at room temperature with hydrogen. The catalyst was then separated using a filter with suction and the reaction solution
dryppet til en oppløsning av 0,3 6 g (9,5 mmol) natriumborhydrid i 25 ml dimetylacetamid ved 15°C i løpet av 1 time. dropped into a solution of 0.36 g (9.5 mmol) of sodium borohydride in 25 ml of dimethylacetamide at 15°C over 1 hour.
Det ble etter-omrørt i 1 time ved romtemperatur, og reak-sjonsoppløsningen ble surgjort med en blanding av 0,65 g maur-syre og 25 ml metanol. Løsningsmidlene ble avdampet i vann-stråle-vakuum, og residuet ble opptatt i 30 ml vann. It was then stirred for 1 hour at room temperature, and the reaction solution was acidified with a mixture of 0.65 g of formic acid and 25 ml of methanol. The solvents were evaporated in a water-jet vacuum, and the residue was taken up in 30 ml of water.
Den vandige oppløsning ble påsatt på 40 g sterkt sur kationebytter og deretter på 40 g svakt basisk anionebytter. Deretter ble den vandige oppløsning behandlet med 0,5 g aktivt kull. The aqueous solution was applied to 40 g of strongly acidic cation exchange and then to 40 g of weakly basic anion exchange. The aqueous solution was then treated with 0.5 g of activated carbon.
Etter fraskillelse av det aktive kull på filter med sug og inndamping av den vandige oppløsning fikk man 2,0 g hvitt krystallinsk produkt med smp. 153-154°C. After separation of the activated carbon on a filter with suction and evaporation of the aqueous solution, 2.0 g of white crystalline product with m.p. 153-154°C.
C8<H>13<N>3°4(215,21) beregnet C 44,7 H 6,1 N 19,5 C8<H>13<N>3°4(215.21) calculated C 44.7 H 6.1 N 19.5
funnet C 44,6 H6,3 N 19,1 found C 44.6 H6.3 N 19.1
<i>H-NMR: (DMS0-d6, 300 MHz) S i ppm<i>H-NMR: (DMS0-d6, 300 MHz) S in ppm
8,10 ^(br. t, J = 5,8 Hz, 1H)8.10 ^(br. t, J = 5.8 Hz, 1H)
7,317(br. s, 1H) 7,317(br. s, 1H)
7,06((br. s, 1H)7.06((br. s, 1H)
5,21 (d, J = 4,0 Hz, 1H) 5.21 (d, J = 4.0 Hz, 1H)
4,30 (m, 1H) 4.30 (m, 1H)
3,89 (d, J = 16,4 Hz, 1H) 3.89 (d, J = 16.4 Hz, 1H)
3,77 (d, J = 16,4 Hz, 1H) 3.77 (d, J = 16.4 Hz, 1H)
3,66 (d, J =5,8Hz, 2H) 3.66 (d, J =5.8Hz, 2H)
3,62 (dd, J = 5,5 Hz, J = 10,6 Hz, 1H)3.62 (dd, J = 5.5 Hz, J = 10.6 Hz, 1H)
3,18 (dd, J = 2,5 Hz, J = 10,6 Hz, 1H)3.18 (dd, J = 2.5 Hz, J = 10.6 Hz, 1H)
2,57 (dd, J = 7,0 Hz, J = 16,6 Hz, 1H)2.57 (dd, J = 7.0 Hz, J = 16.6 Hz, 1H)
2,09 (dd, J = 2,8 Hz, J = 16,6 Hz, 1H) 2.09 (dd, J = 2.8 Hz, J = 16.6 Hz, 1H)
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH291987 | 1987-07-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO883381D0 NO883381D0 (en) | 1988-07-29 |
| NO883381L true NO883381L (en) | 1989-01-31 |
Family
ID=4244565
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO88883381A NO883381L (en) | 1987-07-30 | 1988-07-29 | PROCEDURE FOR THE PREPARATION OF N - (((4-HYDROSY-PYRROLIDIN-2-ON-1-YL) -ACETYL) -GYLCINAMIDE. |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0301398A3 (en) |
| JP (1) | JPS6450894A (en) |
| DK (1) | DK356288A (en) |
| HU (1) | HUT47597A (en) |
| IL (1) | IL87216A0 (en) |
| NO (1) | NO883381L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH680293A5 (en) * | 1990-06-26 | 1992-07-31 | Lonza Ag |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1190378B (en) * | 1985-06-21 | 1988-02-16 | Isf Spa | PYROLIDONIC DERIVATIVES |
| IL80071A0 (en) * | 1985-09-24 | 1986-12-31 | Lonza Ag | Pyrrolidine acetamide derivatives |
| HU195773B (en) * | 1985-09-24 | 1988-07-28 | Lonza Ag | Process for preparing alkyl esters of 4-alkoxy-3-pyrrolin-2-on-1-yl-acetic acid |
-
1988
- 1988-06-28 DK DK356288A patent/DK356288A/en not_active Application Discontinuation
- 1988-07-20 EP EP88111706A patent/EP0301398A3/en not_active Withdrawn
- 1988-07-26 IL IL87216A patent/IL87216A0/en unknown
- 1988-07-26 JP JP63186669A patent/JPS6450894A/en active Pending
- 1988-07-29 NO NO88883381A patent/NO883381L/en unknown
- 1988-07-29 HU HU884039A patent/HUT47597A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0301398A2 (en) | 1989-02-01 |
| EP0301398A3 (en) | 1990-05-30 |
| JPS6450894A (en) | 1989-02-27 |
| DK356288D0 (en) | 1988-06-28 |
| IL87216A0 (en) | 1988-12-30 |
| HUT47597A (en) | 1989-03-28 |
| NO883381D0 (en) | 1988-07-29 |
| DK356288A (en) | 1989-01-31 |
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